Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors

• Published in: European journal of medicinal chemistry Vol. 45; no. 6; pp. 2578 - 2590
• Main Authors: Choi, Soo-Jeong, Cho, Joong-Heui, Im, Isak, Lee, So-Deok, Jang, Ji-Yeon, Oh, Yu-Min, Jung, Yong-Keun, Jeon, Eun-Seok, Kim, Yong-Chul
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.06.2010; Elsevier
• Subjects: 1,4-Dihydropyridine; Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; BACE-1 inhibitors; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; Drug Design; Hydroxyethylamine; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Science & Technology; APP; 1,4-Dihydropyridine; PyBOP; SAR; CNS; BSA; DMEM; THF; BACE-1; DIPA; FBS; DMAP; APPsβ; HATU; DMF; Alzheimer's disease; 1,4-DHP; EDAC; AD; Hydroxyethylamine; HEA; DIPEA; Aβ 40; pNPP; Bn; Aβ 42; AP; DCM; HEK; TEA; BACE-1 inhibitors; POTENT; HUMAN BETA-SECRETASE; PROGRESS; PEPTIDOMIMETIC INHIBITORS; AMYLOID PRECURSOR PROTEIN; CLEAVAGE; Aminoalcohol; Cyclopropane derivatives; Enzyme; Alzheimer disease; Enzyme inhibitor; Binding site; Antialzheimer agent; In vitro; Modeling; Biological activity; Amyloid precursor protein; Peptidases; Molecular model; Hydrolases; Carboxamide; Aspartic endopeptidases; Dihydropyridine derivatives; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.02.046

BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC 50 values in the range 8–30 μM, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors. [Display omitted]